Judith L. Toffenetti, Ph.D. Partner McDermott, Will & Emery, LLP
Atabak R. Royaee, Ph.D.
As the need for transplantable organs is as dire as ever, the question of patent eligibility for bioprinted organs arises.
Despite advances in healthcare and medicine, every year more patients become candidates for organ replacement. Organs that are on high demand for transplantation include kidney, liver, heart, pancreas, lung, and intestine. According to the U.S. Department of Health and Human Services, the recurring theme every year is the imbalance between the supply of organs and the number of patients who could benefit from transplantation. The supply of organs, which is mainly through donations, simply cannot keep up with the demand.
With laws generally prohibiting the sale and trafficking of human organs for profit, scientists in the field of tissue engineering and regenerative medicine worked over the last few decades to develop new methods for obtaining human organs and tissues suitable for transplantation. The latest technology that is being tested is 3D printing, also known as bioprinting, to generate functional three-dimensional human organs.
Bioprinting technology, in general, involves depositing consecutive layers of adult or embryonic stem cells as “bio-ink” in a desired pattern and controlling cell aggregations, fusions and differentiations until a living three-dimensional structure with specialized compartments (such as cavities and vasculature) and specialized cell types (such as smooth muscle cells, endothelial cells, connective tissue cells, lung cells or liver cells) is produced. There have been reports in the scientific literature that various groups have succeeded in printing skin, bone, blood vessel, and ears. Printing of complex organs such kidney and pancreas may be feasible in the future. According to some estimates, any printed organs will likely be different in shape from the naturally occurring organs (e.g., tube-like), due to the methodology used in printing.
This exciting new technology raises a fundamental issue from the perspective of patent law. Is a human organ or other human tissues created by printing of naturally occurring human cells patent-eligible subject matter, or are such organs and tissues merely products of nature and thus, not patent-eligible subject matter?
The Chakrabarty Test
Under the U.S. patent system, in exchange for public disclosure of an invention, a patent owner is given the right, for a limited time, to exclude others from making, using, offering to sell, selling or importing into the U.S. the patented product. The patent claims provide public notice of the boundaries of what was invented and is protected by the patent. For example, a patent claim directed to a bioprinted kidney would exclude others from making, using, offering to sell, selling or importing into the U.S. any other bioprinted kidneys that meet the claim limitations regardless of the methods by which these other bioprinted kidneys were made. There are a series of requirements that a patent claim must meet to be found patentable. These requirements include utility, novelty, obviousness, and satisfying written description and enablement requirements, which are codified under sections 101, 102, 103, and 112, respectively, of Title 35 of the United States Code (“the Patent Act”). This article examines only the utility requirement under section 101 of the Patent Act, which deals with the question of whether or not a claim encompasses patent-eligible subject matter.
Section 101 of the Patent Act states that “whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent. . . .” In a landmark decision in Diamond v. Chakrabarty,1 the Supreme Court interpreted the statutory language of section 101 to include “anything under the sun that is made by man.”2 However, the Court carved out a few exceptions from this general rule: laws of nature, products of nature, physical or natural phenomenon, abstract ideas, and unapplied mathematical formula do not constitute patentable subject matter.3 These exceptions relate to “basic tools of scientific and technological work”,4 which are a “manifestation of . . . nature free to all men and reserved exclusively to none.”5
In Chakrabarty, the Court addressed whether or not a genetically engineered micro-organism—which unlike any naturally occurring bacteria was capable of breaking down multiple components of crude oil—was a “product of nature.” The Court held that the engineered bacterium was patent-eligible subject matter because it was “a nonnaturally occurring manufacture or composition of matter—a product of human ingenuity ‘having a distinctive name, character [and] use.’”6 Thus, based on the framework set forth in Chakrabarty, which is applicable to all biotechnology-related subject matters, to avoid the “product of nature” exception, a manufacture or a composition of matter must be (1) nonnaturally occurring (“with markedly different characteristics from any found in nature”)7 and (2) it must be a product of human ingenuity.
In 2013, based on this two-prong test, the Supreme Court held in Association for Molecular Pathology v. Myriad8 that an isolated DNA fragment (whether physically isolated or chemically synthesized) was not patent-eligible subject matter because (1) mere isolation of the DNA from its surrounding genetic material did not significantly add to the natural state of DNA and thus, was still a naturally occurring composition of matter and (2) its genetic information was neither created nor altered to qualify it as a product of human ingenuity.
Chakrabarty and Bioprinting
Although, at first glance, bioprinted organs appear to be no more than an assembly of naturally occurring cells in a 3D structure, but under the Chakrabarty two-prong test it becomes clear that such manufactures constitute patent-eligible subject matter. The first prong of the Chakrabarty test asks whether or not a bioprinted organ is a naturally occurring manufacture. The Supreme Court has defined the term “manufacture” as “the production of articles for use from raw or prepared materials by giving to these materials new forms, qualities, properties, or combinations, whether by hand-labor or by machinery.”9 Based on this definition, a bioprinted organ is a “manufacture,” but is it also naturally occurring? Given the current state of bioprinting of organs and tissues, the answer to this question is a resounding “yes”.
The current state of the art in the field of regenerative medicine is directed to (1) the 3D printing of biocompatible cell-free solid scaffolds (e.g., cellulose) in the shape of an organ (e.g., an ear) that can act as a support for human cells (e.g., cartilage or skin cells) to then adhere to and naturally grow on them; (2) the 3D printing of cellularized scaffolds that allows for fabrication of structures with two or more cell types located at precise locations (e.g., a joint structure with bone and cartilage portions);10 (3) the 3D bioprinting of tissue and organs without the need for solid supports.11
In general, 3D bioprinting of tissues and organs without solid scaffolds involves sequential depositing of layers of a soft biocompatible matrix (e.g., elastin, collagen) into which stem cells are printed in a nonrandom predetermined pattern. The printed cells of each layer are subsequently differentiated into a specialized cell type (e.g., muscle cells, umbrella cells, urotheliel cells of bladder) and allowed to fuse to cells of the adjacent layers to form a multilayer structure resembling a human tissue or organ (e.g., human bladder). A recently issued patent to bioprinted organs includes the following claim: a three-dimensional layered structure comprising at least one layer of a matrix; and a plurality of cell aggregates, each cell aggregate comprising a plurality of living cells, wherein the cell aggregates are embedded in at least one layer of matrix in a nonrandom predetermined pattern, the cell aggregates having predetermined positions in the pattern.12 Alternatively, some groups have claimed the bioprinted organs as engineered, living, three-dimensional connective tissue constructs comprising connective tissue cells cohered to one another to provide a living, three-dimensional connective tissue construct, wherein the construct is substantially free of preformed scaffold at the time of use.13
The Supreme Court has recognized that “[g]roundbreaking, innovative, or even brilliant discovery does not by itself satisfy the §101 inquiry, [nor does] extensive effort alone.”14 Although an extensive research effort is required to isolate and propagate the naturally occurring stem cells for using them in an iterative process of printing, growing, differentiating, etc., the research efforts play no role in a section 101 patent eligibility inquiry. However, given the current state of the art, bioprinted tissues and organs appear to be significantly different from their current human counterparts. The structural differences between a bioprinted organ and a parent organ clearly are significant. For example, state of the art of bioprinting technology cannot generate innervated organs. Currently, the printed organs do not contain vasculature and are composed primarily homogeneous cells or at best, layers of different cell types. These structural differences from their human counterparts are significant. Although the individual cells of a bioprinted organ are naturally occurring, their assembly into a functional organ is not.
The second prong of the Chakrabarty test asks whether the bioprinted organ or tissue is a product of human ingenuity, which is subject to some of the same considerations associated with the first prong of the Chakrabarty test. In Chakrabarty, the genetic alteration that rendered the bacteria functionally different from any other naturally occurring bacteria (i.e., the ability to biodegrade oil) convinced the Court that the engineered bacteria were a product of human ingenuity. In Myriad, a DNA fragment that lacked any genetic alterations but was isolated from a larger, naturally occurring DNA stretch was found not to be a product of human ingenuity. Unlike DNA, a bioprinted organ is distinct from the naturally occurring product and is certainly a product of human ingenuity. Without human intervention, stem cells cannot self-assemble into a uniform structure in vitro, let alone function as an organ. Thus, a bioprinted organ would most likely satisfy the second prong of the Chakrabarty test.
In summary, although a bioprinted organ may contain cells that are genetically identical to a naturally occurring counterpart, the organ itself is patent-eligible subject matter because of its novel functional and structural properties. The Supreme Court in Myriad cautioned that “[t]he rule against patents on naturally occurring things is not without limits, however, for all inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or abstract ideas,” and “too broad an interpretation of this exclusionary principle could eviscerate patent law.”15 Thus, a court should find that the structural and/or functional differences between bioprinted organs and naturally occurring cells or organs are sufficient enough to satisfy the requirement of 35 U.S.C. § 101. However, just having patent-eligible subject matter does not automatically make a claim to a bioprinted organ patentable. Other requirements such as novelty, obviousness, written description, and enablement must still be satisfied before the claim is found patentable.
Want more on bioprinting? Be sure to check out “Bioprinting: From Patches to Parts” from our May 15 issue.
Judith L. Toffenetti, Ph.D., is a partner in the law firm of McDermott Will & Emery LLP. Atabak R. Royaee, Ph.D., is an associate in the law firm of McDermott Will & Emery LLP and is based in the firm's Washington, DC, office.
1 Diamond v. Chakrabarty 447 U.S. 303 (1980).
2 Id. at 309.
4 Mayo v. Prometheus 566 U.S. 10-1150 (2012)
5 See Supra note 1.
8 Association for Molecular Pathology v. Myriad 569 U. S. 12–398 (2013).
9 Chakrabarty, 447 U.S. 303 at 308 (citing Shell Development Co. v. Watson, 149 F.Supp, 279, 280 (D.C. 1957)(citing 1A. Deller, Walker on Patents § 14, p. 55 (1st ed. 1937))).
11 US8241905 and US20140099709.
12 U.S. Patent 8,241,905.
13 U.S. Patent Application No. 20140099709.
14 See Supra note 8.